Abstract CT105: Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver
Authors: Sarbajit Mukherjee, Patrick M. Boland, Melissa Grimm, Ronald Slomba, Kristopher Attwood, Renuka Iyer, Pawel Kalinski
Journal: Cancer Research (2022)

Abstract Background: Liver metastases develop in 20-50% of colorectal cancer (CRC) patients, being typically resistant to immune checkpoint inhibitors (ICIs) and having a poor prognosis. Our preliminary data showed synergy between IFNα and TLR3 ligands in selectively enhancing the intratumoral production of CD8+ T cell (CTL) attracting chemokines (but not Treg attractants) in ex vivo-treated CRC explants and preferential impact of this combination on liver-metastatic CRC tumor tissues (rather than surrounding liver tissues). Based on these data and previous reports showing the prognostic value of intratumoral CTLs in the CRC outcomes, we hypothesized that systemic infusion of the combination of IFNα2b with rintatolimod (selective TLR3 ligand for i.v. use) can reprogram local balance between the CTL- and regulatory T cell (Treg)-attracting chemokines and the resulting patterns of immune infiltrate in liver lesions. Methods: Recurrent/metastatic CRC patients with unresectable liver metastases amenable to biopsy were eligible. Patients had prior treatment (Rx) with fluoropyrimidine, irinotecan, oxaliplatin, and an anti-EGFR targeted therapy (if RAS wt), or contra-indication to such. Patients received IFNα2b IV (20 million units/m2 IV daily) and rintatolimod (200 mg IV daily) plus oral celecoxib (200 mg twice daily) on days 1, 2, 3, 8, 9, 10, 15, 16, and 17. Response assessment was done via liver biopsies (pre-Rx and on day 24 ± 4 days) and CT imaging (RECIST v1.1) on D46. The primary endpoint was the change in CD8+ T-cells before Rx, with that seen post-Rx (measured by quantitative RT-PCR as a ratio of CD8α to a housekeeping gene, HPRT). With a sample size of N=12 evaluable pts, the study design had a 90% power to detect a 0.77 standard deviation increase (pre- to post Rx) at a significance level of 0.1 (ClinicalTrials.gov Identifier: NCT03403634). Results: Nineteen patients with microsatellite stable (MSS) CRC were enrolled between Apr 2018 and Oct 2020, 15 were treated and 12 were evaluable for the primary endpoint. Most were male (75%, N=9) and Caucasian (92%, N=11). The median age at diagnosis was 65 years. Most had previously received three or more prior lines of therapy (58%, N=7). The study's primary endpoint was met, evidenced by increased CD8a expression post-treatment (p=0.046). An increase in ratios of CD8a/CD4 (p=0.03), CD8a/FOXP3 (p&amp;lt;0.01) and GZMB/FOXP3 (p&amp;lt;0.01) was observed. The expression of CTL-attracting chemokines CCL5 (p=0.08), CXCL9 (p=0.05), and CXCL10 (p=0.06) were increased, while expression of the Treg/MDSC attractant CXCL12 (p=0.07) was decreased post-Rx. Median OS was 10.5 (90% CI 2.2-15.2) months, and the median PFS was 1.5 (90% CI 1.4, 1.8) months. No objective response was seen. The treatment was well tolerated. Of all enrolled patients (N=19), adverse events were noted in 74% of patients, with the most common being fatigue (58%). Grade 3 or higher adverse events were rare (5%). Age, gender, line of treatment, RAS mutational status, and tumor location did not significantly impact CD8a change or PFS. Conclusion: Our study demonstrated that a combinatorial CKM regimen could re-program the immunosuppressive tumor microenvironment in MSS CRC patients with liver metastasis, raising the possibility that the CKM regimen can be used to enhance the effectiveness of ICIs in this group of patients. Citation Format: Sarbajit Mukherjee, Patrick M. Boland, Melissa Grimm, Ronald Slomba, Kristopher Attwood, Renuka Iyer, Pawel Kalinski. Initial results of a phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer metastatic to the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT105.